Porous drug matrices and methods of manufacture thereof

ABSTRACT

Drugs, especially low aqueous solubility drugs, are provided in a porous matrix form, preferably microparticles, which enhances dissolution of the drug in aqueous media. The drug matrices preferably are made using a process that includes (i) dissolving a drug, preferably a drug having low aqueous solubility, in a volatile solvent to form a drug solution, (ii) combining at least one pore forming agent with the drug solution to form an emulsion, suspension, or second solution, and (iii) removing the volatile solvent and pore forming agent from the emulsion, suspension, or second solution to yield the porous matrix of drug. The pore forming agent can be either a volatile liquid that is immiscible with the drug solvent or a volatile solid compound, preferably a volatile salt. In a preferred embodiment, spray drying is used to remove the solvents and the pore forming agent. The resulting porous matrix has a faster rate of dissolution following administration to a patient, as compared to non-porous matrix forms of the drug. In a preferred embodiment, microparticles of the porous drug matrix are reconstituted with an aqueous medium and administered parenterally, or processed using standard techniques into tablets or capsules for oral administration.

CROSS-REFERENCE TO RELATED APPLICATIONS

Priority is claimed to U.S. provisional applications Ser. No.60/136,323, filed May 27, 1999, and Ser. No. 60/158,659, filed Oct. 8,1999.

BACKGROUND OF THE INVENTION

This invention generally relates to formulations of drugs, especiallydrugs having low solubility, and more particularly to methods of makingformulations of such drugs to enhance their rate of dissolution.

The bioavailability of a drug can be limited by poor dissolution of thedrug into aqueous bodily fluids following administration. Thisrate-limiting step may therefore be critical to rapidly attainingtherapeutically effective drug levels.

Traditional approaches to parenteral delivery of poorly soluble drugsinclude using large volumes of aqueous diluents, solubilizing agents,detergents, non-aqueous solvents, or non-physiological pH solutions.These formulations, however, can increase the systemic toxicity of thedrug composition or damage body tissues at the site of administration.

Other approaches have focused on the physical form of the drug itself.Since the dissolution rate of a drug particle is directly related to itssurface area available to contact the aqueous media at the site ofadministration or site of absorption, methods of preparing drugs innanoparticulate form have been developed in an effort to maximize thedrug surface area, as described, for example, in U.S. Pat. No. 5,534,270to De Castro and U.S. Pat. No. 5,587,143 to Wong. Nanoparticles,however, can be difficult to produce and maintain in a stable form dueto the tendency of the nanoparticles to flocculate or agglomerate,particularly without the presence of surface modifying agents adsorbedor coated onto the particles. Furthermore, milling or wet grindingtechniques, which are typically employed for nanonization, can beundesirable, as it can take several days to process a single batch,scaling-up of the milling or grinding process can be difficult and/orcostly, the process can be difficult to conduct aseptically, and it isdifficult to eliminate shedding of milling media into the product.

Other efforts directed at enhancing the rate of dissolution have focusedon delivering the drug as a dispersion in a water-soluble orbiodegradable matrix, typically in the form of polymeric microparticles.For example, the dissolution rate of dexamethasone reportedly wasimproved by entrapping the drug in chitosan microspheres made byspray-drying (Genta, et al., S.T.P. Pharma Sciences 5(3):202-07 (1995)).Similarly, others have reported enhanced dissolution rates by mixing apoorly soluble drug powder with a water-soluble gelatin, whichpurportedly makes the surface of the drug hydrophilic (Imai, et al., JPharm. Pharmacol, 42:615-19 (1990)).

Related efforts have been directed to forming relatively large, porousmatrices of low solubility drugs. For example, Roland &Paeratakul,“Spherical Agglomerates of Water-Insoluble Drugs,” J Pharma.Sci., 78(11):964-67 (1989) discloses preparing beads having a lowsolubility drug content up to 98%, wherein the beads have a porousinternal structure. Such large beads, however, are unsuitable forparenteral administration, and the beads have less surface area andslower dissolution rates than smaller particles.

It is therefore an object of the present invention to providecompositions enhancing the dissolution rate of drugs, especially drugshaving low aqueous solubility, and to provide methods of making suchcompositions.

It is another object of the present invention to provide compositionsproviding enhanced dissolution of drugs, especially drugs of low aqueoussolubility, in a formulation suitable for administration by a variety ofroutes, including, but not limited to, parenteral, mucosal, oral, andtopical administration, for local, regional, or systemic effect.

It is further object of the present invention to provide compositionsfor administration as a bolus injection instead of by infusion.

SUMMARY OF THE INVENTION

Drugs are provided in a porous matrix form wherein the dissolution rateof the drug is enhanced when the matrix is contacted with an aqueousmedium. In a preferred embodiment, low aqueous solubility drugs areprovided in a porous matrix form which forms microparticles when thematrix is contacted with an aqueous medium. The porous matrix with lowaqueous solubility drugs yields upon contact with an aqueous mediummicroparticles having a mean diameter between about 0.1 and 5 μm and atotal surface area greater than about 0.9 m²/mL. The dry porous matrixis in a dry powder form having a TAP density less than or equal to 1.0g/mL and/or having a total surface area (sum of internal and externalsurface area) of greater than or equal to 0.2 m²/g. The porous matricesthat contain the drug are preferably made using a process that includes(i) dissolving a drug in a volatile solvent to form a drug solution,(ii) combining at least one pore forming agent with the drug solution toform an emulsion, suspension, or second solution, and (iii) removing thevolatile solvent and pore forming agent from the emulsion, suspension,or second solution to yield the dry porous matrix of drug. The resultingporous matrix has a faster rate of dissolution following administrationto a patient, as compared to non-porous matrix forms of the drug. Thepore forming agent can be either a volatile liquid that is immisciblewith the drug solvent or a volatile solid compound, preferably avolatile salt. If the pore forming agent is a liquid, the agent isemulsified with the drug solution. If the pore forming agent is a solid,the agent is (i) dissolved in the drug solution, (ii) dissolved in asolvent that is not miscible in the drug solvent and then emulsifiedwith the drug solutions or iii suspended as solid particulates in thedrug solution. Optionally, hydrophilic excipients, wetting agents,and/or tonicity agents may be added to the drug solvent, the poreforming agent solvent, or both. The solution, emulsion, or suspension ofthe pore forming agent in the drug solution is then processed to removethe drug solvent and the pore forming agent, as well as any pore formingagent solvent. In a preferred embodiment, spray drying, optionallyfollowed by lyophilization, fluid bed drying, or vacuum drying, is usedto remove the solvents and the pore forming agent.

An advantage of the formulations is that they can be administered as abolus, when the drug normally must be infused to avoid precipitation ofthe drug. By avoiding precipitation of drug in vivo, the formulationscan also be administered parenterally. An additional advantage is theformulations can be administered in reduced volumes.

In one embodiment, the matrix further includes a pegylated excipient,such as pegylated phospholipid, with the drug. The pegylated excipientshields the drug from macrophage uptake, which prolong its half-life orenhance bioavailability of the drug.

In a preferred embodiment, the porous drug matrix is reconstituted withan aqueous medium and administered- parenterally, such asintramuscularly, isubcutaneously, or intravenously. Alternatively, theporous drug matrix can be further processed using standard techniquesinto tablets or capsules for oral administration or into rectalsuppositories, delivered using a dry powder inhaler for pulmonaryadministration, or mixed/processed into a cream or ointment for topicaladministration.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph of the in vitro dissolution rate (percent dissolvedversus time) for non-formulated prednisone and prednisone in porousmatrix form.

FIG. 2 is a graph of the in vitro dissolution rate (percent dissolvedversus time) for non-formulated griseofulvin and griseofulvin in porousmatrix form.

FIG. 3 is a graph of the in vitro dissolution rate (percent dissolvedversus time) for non-formulated nifedipine and nifedipine in porousmatrix form.

FIG. 4 is a graph of the in vitro dissolution rate (percent dissolvedversus time) for non-formulated naproxen and naproxen in a porous matrixform.

FIG. 5 is a graph of the in vitro dissolution rate (percent dissolvedversus time) for non-formulated paclitaxel and paclitaxel in a porousmatrix form.

FIG. 6 is a graph of the in vitro dissolution rate (percent dissolvedversus time) for various porous matrix forms of nifedipine.

FIG. 7 is a graph of the in vitro dissolution rate (percent dissolvedversus time) for various porous matrix forms of griseofulvin.

FIG. 8 is a graph of nifedipine plasma levels versus time postintravenous administration of reconstituted nifedipine matrix in dogs.

DETAILED DESCRIPTION OF THE INVENTION

The rate of dissolution of drugs can be enhanced by making the drug intoa porous matrix form, substantially increasing the surface area of thedrug available to contact aqueous biological fluids at the site ofadministration of the drug composition. In a preferred embodiment, thedrug has low aqueous solubility.

I. Drug Matrix Compositions

The porous drug matrix is at least 1 to 95%, preferably at least about10%, and more preferably between about 10 and 60%, drug by weight. Thematrices also may contain hydrophilic excipients such as water solublepolymers or sugars, wetting agents such as surfactants, and tonicityagents.

The form of the drug matrix (drug powder) is critical to the dissolutionrate. The matrix must contain microparticles of drug, which preferablyhave a diameter between about 100 nm and 5 μm, more preferably betweenabout 500 nm and 5 μm. The average total surface area of themicroparticles contained within the porous matrix, which typically is inthe form of a dry powder, is 0.9 m²/mL or greater. Total surface areavalues can be determined using standard Coulter Counter equipment andtechniques.

The drug matrix must be sufficiently porous to yield microparticleshaving these parameters. Measurements useful in characterizing theporosity of the drug matrix are the bulk density or the transaxialpressure (“TAP”) density of the dry porous matrix (dry powder) and thetotal surface area (sum of internal and external surface area) of thedry porous matrix . The TAP density preferably is less than about 1.0g/ml, more preferably less than 0.8 g/ml. This level of porosity of thematrix, characterized by density, provides sufficient surface area toenhance wetting of the dry porous matrix and enhance drug dissolution.The total surface area of the porous matrix can be measured, forexample, by BET surface area analysis. The total surface area of theporous matrix preferably is greater than 0.1 m²/g, more preferablygreater than or equal to 0.2 m²/g. This level of total surface areaprovides sufficient surface area to enhance wetting of the dry porousmatrix and enhance drug dissolution.

1. Drugs

A wide variety drugs are useful in the methods and compositionsdescribed herein. In a preferred embodiment, the drug is a low aqueoussolubility drug. As used herein, the term“low aqueous solubility” meansthat the drug has a solubility of less than about 10 mg/mL, andpreferably less than about 5 mg/mL, in aqueous media at approximatelyphysiological temperatures and pH. As used herein, the term“drug” refersto chemical or biological molecules providing a therapeutic, diagnostic,or prophylactic effect in vivo.

Drugs contemplated for use in the compositions described herein includethe following categories and examples of drugs and alternative forms ofthese drugs such as alternative salt forms, free acid forms, free baseforms, and hydrates:

analgesics/antipyretics (e.g., aspirin, acetaminophen, ibuprofen,naproxen sodium, buprenorphine, propoxyphene hydrochloride, propoxyphenenapsylate, meperidine hydrochloride, hydromorphone hydrochloride,morphine, oxycodone, codeine, dihydrocodeine bitartrate, pentazocine,hydrocodone bitartrate, levorphanol, diflunisal, trolamine salicylate,nalbuphine hydrochloride, mefenamic acid, butorphanol, cholinesalicylate, butalbital, phenyltoloxamine citrate, diphenhydraminecitrate, methotrimeprazine, cinnamedrine hydrochloride, andmeprobamate);

antiasthamatics (e.g., ketotifen and traxanox);

antibiotics (e.g., neomycin, streptomycin, chloramphenicol,cephalosporin, ampicillin, penicillin, tetracycline, and ciprofloxacin);

antidepressants (e.g., nefopam, oxypertine, doxepin, amoxapine,trazodone, amitriptyline, maprotiline, phenelzine, desipramine,nortriptyline, tranylcypromine, fluoxetine, doxepin, imipramine,imipramine pamoate, isocarboxazid, trimipramine, and protriptyline);

antidiabetics (e.g., biguanides and sulfonylurea derivatives);

antifungal agents (e.g., griseofulvin, ketoconazole, itraconizole,amphotericin B, nystatin, and candicidin);

antihypertensive agents (e.g., propanolol, propafenone, oxyprenolol,nifedipine, reserpine, trimethaphan, phenoxybenzamine, pargylinehydrochloride, deserpidine, diazoxide, guanethidine monosulfate,minoxidil, rescinnamine, sodium nitroprusside, rauwolfia serpentina,alseroxylon, and phentolamine);

anti-inflammatories (e.g., (non-steroidal) indomethacin, ketoprofen,flurbiprofen, naproxen, ibuprofen, ramifenazone, piroxicam, (steroidal)cortisone, dexamethasone, fluazacort, celecoxib, rofecoxib,hydrocortisone, prednisolone, and prednisone);

antineoplastics (e.g., cyclophosphamide, actinomycin, bleomycin,daunorubicin, doxorubicin, epirubicin, mitomycin, methotrexate,fluorouracil, carboplatin, carmustine (BCNU), methyl-CCNU, cisplatin,etoposide, camptothecin and derivatives thereof, phenesterine,paclitaxel and derivatives thereof, docetaxel and derivatives thereof,vinblastine, vincristine, tamoxifen, and piposulfan);

antianxiety agents (e.g., lorazepam, buspirone, prazepam,chlordiazepoxide, oxazepam, clorazepate dipotassium, diazepam,hydroxyzine pamoate, hydroxyzine hydrochloride, alprazolam, droperidol,halazepam, chlormezanone, and dantrolene);

immunosuppressive agents (e.g., cyclosporine, azathioprine, mizoribine,and FK506 (tacrolimus));

antimigraine agents (e.g., ergotamine, propanolol, isometheptene mucate,and dichloralphenazone);

sedatives/hypnotics (e.g., barbiturates such as pentobarbital,pentobarbital, and secobarbital; and benzodiazapines such as flurazepamhydrochloride, triazolam, and midazolam);

antianginal agents (e.g., beta-adrenergic blockers; calcium channelblockers such as nifedipine, and diltiazem; and nitrates such asnitroglycerin, isosorbide dinitrate, pentaerythritol tetranitrate, anderythrityl tetranitrate);

antipsychotic agents (e.g., haloperidol, loxapine succinate, loxapinehydrochloride, thioridazine, thioridazine hydrochloride, thiothixene,fluphenazine, fluphenazine decanoate, fluphenazine enanthate,trifluoperazine, chlorpromazine, perphenazine, lithium citrate, andprochlorperazine);

antimanic agents (e.g., lithium carbonate);

antiarrhythmics (e.g., bretylium tosylate, esmolol, verapamil,amiodarone, encainide, digoxin, digitoxin, mexiletine, disopyramidephosphate, procainamide, quinidine sulfate, quinidine gluconate,quinidine polygalacturonate, flecainide acetate, tocainide, andlidocaine);

antiarthritic agents (e.g., phenylbutazone, sulindac, penicillanine,salsalate, piroxicam, azathioprine, indomethacin, meclofenamate, goldsodium thiomalate, ketoprofen, auranofin, aurothioglucose, and tolmetinsodium);

antigout agents (e.g., colchicine, and allopurinol);

anticoagulants (e.g., heparin, heparin sodium, and warfarin sodium);

thrombolytic agents (e.g., urokinase, streptokinase, and alteplase);

antifibrinolytic agents (e.g., aminocaproic acid);

hemorheologic agents (e.g., pentoxifylline);

antiplatelet agents (e.g., aspirin);

anticonvulsants (e.g., valproic acid, divalproex sodium, phenytoin,phenytoin sodium, clonazepam, primidone, phenobarbitol, carbamazepine,amobarbital sodium, methsuximide, metharbital, mephobarbital,mephenytoin, phensuximide, paramethadione, ethotoin, phenacemide,secobarbitol sodium, clorazepate dipotassium, and trimethadione);

antiparkinson agents (e.g., ethosuximide);

antihistamines/antipruritics (e.g., hydroxyzine, diphenhydramine,chlorpheniramine, brompheniramine maleate, cyproheptadine hydrochloride,terfenadine, clemastine fumarate, triprolidine, carbinoxamine,diphenylpyraline, phenindamine, azatadine, tripelennamine,dexchlorphenirarnine maleate, methdilazine, and);

agents useful for calcium regulation (e.g., calcitonin, and parathyroidhormone);

antibacterial agents (e.g., amikacin sulfate, aztreonam,chloramphenicol, chloramphenicol palirtate, ciprofloxacin, clindamycin,clindamycin palmitate, clindamycin phosphate, metronidazole,metronidazole hydrochloride, gentamicin sulfate, lincomycinhydrochloride, tobramycin sulfate, vancomycin hydrochloride, polymyxin Bsulfate, colistimethate sodium, and colistin sulfate);

antiviral agents (e.g., interferon alpha, beta or gamma, zidovudine,amantadine hydrochloride, ribavirin, and acyclovir);

antimicrobials (e.g., cephalosporins such as cefazolin sodium,cephradine, cefaclor, cephapirin sodium, ceftizoxime sodium,cefoperazone sodium, cefotetan disodium, cefuroxime e azotil, cefotaximesodium, cefadroxil monohydrate, cephalexin, cephalothin sodium,cephalexin hydrochloride monohydrate, cefamandole nafate, cefoxitinsodium, cefonicid sodium, ceforanide, ceftriaxone sodium, ceftazidime,cefadroxil, cephradine, and cefuroxime sodium; penicillins such asampicillin, amoxicillin, penicillin G benzathine, cyclacillin,ampicillin sodium, penicillin G potassium, penicillin V potassium,piperacillin sodium, oxacillin sodium, bacampicillin hydrochloride,cloxacillin sodium, ticarcillin disodium, azlocillin sodium,carbenicillin indanyl sodium, penicillin G procaine, methicillin sodium,and nafcillin sodium; erythromycins such as erythromycin ethylsuccinate,erythromycin, erythromycin estolate, erythromycin lactobionate,erythromycin stearate, and erythromycin ethylsuccinate; andtetracyclines such as tetracycline hydrochloride, doxycycline hyclate,and minocycline hydrochloride, azithromycin, clarithromycin)

anti-infectives (e.g., GM-CSF);

bronchodilators (e.g., sympathomimetics such as epinephrinehydrochloride, metaproterenol sulfate, terbutaline sulfate, isoetharine,isoetharine mesylate, isoetharine hydrochloride, albuterol sulfate,albuterol, bitolterolmesylate, isoproterenol hydrochloride, terbutalinesulfate, epinephrine bitartrate, metaproterenol sulfate, epinephrine,and epinephrine bitartrate; anticholinergic agents such as ipratropiumbromide; xanthines such as aminophylline, dyphylline, metaproterenolsulfate, and aminophylline; mast cell stabilizers such as cromolynsodium; inhalant corticosteroids such as beclomethasone dipropionate(BDP), and beclomethasone dipropionate monohydrate; salbutamol;ipratropium bromide; budesonide; ketotifen; salmeterol; xinafoate;terbutaline sulfate; triamcinolone; theophylline; nedocromil sodium;metaproterenol sulfate; albuterol; flunisolide; fluticasone proprionate

steroidal compounds and hormones (e.g., androgens such as danazol,testosterone cypionate, fluoxymesterone, ethyltestosterone, testosteroneenathate, methyltestosterone, fluoxymesterone, and testosteronecypionate; estrogens such as estradiol, estropipate, and conjugatedestrogens; progestins such as methoxyprogesterone acetate, andnorethindrone acetate; corticosteroids such as triamcinolone,betamethasone, betamethasone sodium phosphate, dexamethasone,dexamethasone sodium phosphate, dexamethasone acetate, prednisone,methylprednisolone acetate suspension, triamcinolone acetonide,methylprednisolone, prednisolone sodium phosphate, methylprednisolonesodium succinate, hydrocortisone sodium succinate, triamcinolonehexacetonide, hydrocortisone, hydrocortisone cypionate, prednisolone,fludrocortisone acetate, paramethasone acetate, prednisolone tebutate,prednisolone acetate, prednisolone sodium phosphate, and hydrocortisonesodium succinate; and thyroid hormones such as levothyroxine sodium);

hypoglycemic agents (e.g., human insulin, purified beef insulin,purified pork insulin, glyburide, chlorpropamide, glipizide,tolbutarnide, and tolazamide);

hypolipidemic agents (e.g., clofibrate, dextrothyroxine sodium,probucol, pravastitin, atorvastatin, lovastatin, and niacin);

proteins (e.g., DNase, alginase, superoxide dismutase, and lipase);

nucleic acids (e.g., sense or anti-sense nucleic acids encoding anytherapeutically useful protein, including any of the proteins describedherein);

agents useful for erythropoiesis stimulation (e.g., erythropoietin);

antiulcer/antireflux agents (e.g., famotidine, cimetidine, andranitidine hydrochloride);

antinauseants/antiemetics (e.g., meclizine hydrochloride, nabilone,prochlorperazine, dimenhydrinate, promethazine hydrochloride,thiethylperazine, and scopolamine);

oil-soluble vitamins (e.g., vitamins A, D, E, K, and the like);

as well as other drugs such as mitotane, halonitrosoureas,anthrocyclines, and ellipticine. A description of these and otherclasses of useful drugs and a listing of species within each class canbe found in Martindale, The Extra Pharmacopoeia, 30th Ed. (ThePharmaceutical Press, London 1993), the disclosure of which isincorporated herein by reference in its entirety.

Examples of other drugs useful in the compositions and methods describedherein include ceftriaxone, ketoconazole, ceftazidime, oxaprozin,albuterol, valacyclovir, urofollitropin, famciclovir, flutamide,enalapril, mefformin, itraconazole, buspirone, gabapentin, fosinopril,tramadol, acarbose, lorazepan, follitropin, glipizide, omeprazole,fluoxetine, lisinopril, tramsdol, levofloxacin, zafirlukast, interferon,growth hormone, interleukin, erythropoietin, granulocyte stimulatingfactor, nizatidine, bupropion, perindopril, erbumine, adenosine,alendronate, alprostadil, benazepril, betaxolol, bleomycin sulfate,dexfenfluramine, diltiazem, fentanyl, flecainid, gemcitabine, glatirameracetate, granisetron, lamivudine, mangafodipir trisodium, mesalamine,metoprolol fumarate, metronidazole, miglitol, moexipril, monteleukast,octreotide acetate, olopatadine, paricalcitol, somatropin, sumatriptansuccinate, tacrine, verapamil, nabumetone, trovafloxacin, dolasetron,zidovudine, finasteride, tobramycin, isradipine, tolcapone, enoxaparin,fluconazole, lansoprazole, terbinafine, pamidronate, didanosine,diclofenac, cisapride, venlafaxine, troglitazone, fluvastatin, losartan,imiglucerase, donepezil, olanzapine, valsartan, fexofenadine,calcitonin, and ipratropium bromide. These drugs are generallyconsidered to be water soluble.

Preferred drugs include albuterol, adapalene, doxazosin mesylate,mometasone furoate, ursodiol, amphotericin, enalapril maleate,felodipine, nefazodone hydrochloride, valrubicin, albendazole,conjugated estrogens, medroxyprogesterone acetate, nicardipinehydrochloride, zolpidem tartrate, amlodipine besylate, ethinylestradiol, omeprazole, rubitecan, amlodipine besylate/ benazeprilhydrochloride, etodolac, paroxetine hydrochloride, paclitaxel,atovaquone, felodipine, podofilox, paricalcitol, betamethasonedipropionate, fentanyl, pramipexole dihydrochloride, Vitamin D₃ andrelated analogues, finasteride, quetiapine fumarate, alprostadil,candesartan, cilexetil, fluconazole, ritonavir, busulfan, carbamazepine,flumazenil, risperidone, carbemazepine, carbidopa, levodopa,ganciclovir, saquinavir, amprenavir, carboplatin, glyburide, sertralinehydrochloride, rofecoxib carvedilol, halobetasolproprionate, sildenafilcitrate, celecoxib, chlorthalidone, imiquimod, simvastatin, citalopram,ciprofloxacin, irinotecan hydrochloride, sparfloxacin, efavirenz,cisapride monohydrate, lansoprazole, tamsulosin hydrochloride,mofafinil, clarithromycin, letrozole, terbinafine hydrochloride,rosiglitazone maleate, diclofenac sodium, lomefloxacin hydrochloride,tirofiban hydrochloride, telmisartan, diazapam, loratadine, toremifenecitrate, thalidomide, dinoprostone, mefloquine hydrochloride,trandolapril, docetaxel, mitoxantrone hydrochloride, tretinoin,etodolac, triamcinolone acetate, estradiol, ursodiol, nelfinavirmesylate, indinavir, beclomethasone dipropionate, oxaprozin, flutamide,famotidine, nifedipine, prednisone, cefuroxime, lorazepam, digoxin,lovastatin, griseofulvin, naproxen, ibuprofen, isotretinoin, tamoxifencitrate, nimodipine, amiodarone, and alprazolam.

2. Excipients

The matrices may contain hydrophilic excipients such as water solublepolymers or sugars which can serve as bulking agents or as wettingagents, wetting agents such as surfactants or sugars, and tonicityagents. Upon contact with an aqueous medium, water penetrates throughthe highly porous matrix to dissolve the water soluble excipients in thematrix. In the case of low aqueous solubility drugs, a suspension ofdrug particles in the aqueous medium is left. The total surface area ofthe resultant low aqueous solubility drug microparticles is increasedrelative to the unprocessed drug and the dissolution rate of the drug isincreased.

One of skill in the art can select appropriate excipients for use in thedrug matrix compositions, considering a variety of factors, such as thedrug to be administered, the route of administration, the dosage, andthe preferred dissolution rate. For example, the excipients can functionas bulking agents, release-modifiers, wetting agents, tonicity agents,or combinations thereof. Preferred excipients include hydrophilicpolymers, wetting agents, and sugars. The amount of excipient in thedrug matrix is less than about 95%, more preferably less than about 80%,by weight of the drug matrix.

The hydrophilic excipients, wetting agents, and tonicity agents may beadded to the drug solution, the pore forming agent, or both, duringproduction of the matrix.

(i) Hydrophilic Polymers

The polymers that can be used in the drug matrices described hereininclude both synthetic and natural polymers, either non-biodegradable orbiodegradable. Representative synthetic polymers include polyethyleneglycol (“PEG”), polyvinyl pyrrolidone, polymethacrylates, polylysine,poloxamers, polyvinyl alcohol, polyacrylic acid, polyethylene oxide, andpolyethyoxazoline. Representative natural polymers include albumin,alginate, gelatin, acacia, chitosan, cellulose dextran, ficoll, starch,hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxy-propylmethylcellulose, hyaluronic acid, carboxyethyl cellulose, carboxymethylcellulose, deacetylated chitosan, dextran sulfate, and derivativesthereof. Preferred hydrophilic polymers include PEG, polyvinylpyrrolidone, poloxamers, hydroxypropyl cellulose, and hydroxyethylcellulose.

The hydrophilic polymer selected for use in a particular drug matrixformulation is based on a variety of factors, such as the polymermolecular weight, polymer hydrophilicity, and polymer inherentviscosity. The hydrophilic polymer can be used as a bulking agent or asa wetting agent.

(ii) Sugars

Representative sugars that can be used in the drug matrices includemannitol, sorbitol, xylitol, glucitol, ducitol, inositiol, arabinitol;arabitol, galactitol, iditol, allitol, fructose, sorbose, glucose,xylose, trehalose, allose, dextrose, altrose, gulose, idose, galactose,talose, ribose, arabinose, xylose, lyxose, sucrose, maltose, lactose,lactulose, fucose, rhamnose, melezitose, maltotriose, and raffinose.Preferred sugars include mannitol, lactose, sucrose, sorbitol,trehalose, glucose, and are adjusted to provide osmolality ifadministered parenterally or to provide wetting of the porous drugmatrix or the drug microparticles within the matrix.

(iii) Wetting Agents

Wetting agents can be used to facilitate water ingress into the matrixand wetting of the drug particles in order to facilitate dissolution.

Representative examples of wetting agents include gelatin, casein,lecithin (phosphatides), gum acacia, cholesterol, tragacanth, stearicacid, benzalkonium chloride, calcium stearate, glycerol monostearate,cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters,polyoxyethylene alkyl ethers (e.g., macrogol ethers such as cetomacrogol1000), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitanfatty acid esters (e.g., TWEEN™s), polyethylene glycols, polyoxyethylenestearates, colloidal silicon dioxide, phosphates, sodium dodecylsulfate,carboxymethylcellulose calcium, carboxymethylcellulose sodium,methylcellulose, hydroxyethylcellulose, hydroxy propylcellulose,hydroxypropylmethylcellulose phthlate, noncrystalline cellulose,magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, andpolyvinylpyrrolidone (PVP). Tyloxapol (a nonionic liquid polymer of thealkyl aryl polyether alcohol type, also known as superinone or triton)is another useful wetting agent. Most of these wetting agents are knownpharmaceutical excipients and are described in detail in the Handbook ofPharmaceutical Excipients, published jointly by the AmericanPharmaceutical Association and The Pharmaceutical Society of GreatBritain (The Pharmaceutical Press, 1986).

Preferred wetting agents include polyvinylpyrrolidone, polyethyleneglycol, tyloxapol, poloxamers such as PLURONIC™ F68, F127, and F108,which are block copolymers of ethylene oxide and propylene oxide, andpolyxamines such as TETRONIC™ 908 (also known as POLOXAMINE™ 908), whichis a tetraflnctional block copolymer derived from sequential addition ofpropylene oxide and ethylene oxide to ethylenediamine (available fromBASF), dextran, lecithin, dialkylesters of sodium sulfosuccinic acidsuch as AEROSOL™ OT, which is a dioctyl ester of sodium sulfosuccinicacid (available from American Cyanimid), DUPONOL™ P, which is a sodiumlauryl sulfate (available from DuPont), TRITON™ X-200, which is an alkylaryl polyether sulfonate (available from Rohm and Haas), TWEEN™ 20 andTWEEN™ 80, which are polyoxyethylene sorbitan fatty acid esters(available from ICI Specialty Chemicals), Carbowax 3550 and 934, whichare polyethylene glycols (available from Union Carbide), Crodesta F-110,which is a mixture of sucrose stearate and sucrose distearate, andCrodesta SL-40 (both available from Croda Inc.), and SA9OHCO, which isC₁₈H₃₇-CH₂(CON(CH₃)CH₂(CHOH)₄CH₂OH)₂.

Wetting agents which have been found to be particularly useful includeTetronic 908, the Tweens, Pluronic F-68 and polyvinylpyrrolidone. Otheruseful wetting agents include decanoyl-N-methylglucamide;n-decyl-β-D-glucopyranoside; n-decyl-β-D-maltopyranoside;n-dodecyl-β-D-glucopyranoside; n-dodecyl β-D-maltoside;heptanoyl-N-methylglucamide; nheptyl-β-D-glucopyranoside;n-heptyl-β-D-thioglucoside; n-hexyl-β-D-glucopyranoside;nonanoyl-N-methylglucamide; n-noyl-,-D-glucopyranoside;octanoyl-N-methylglucamide; n-octyl-β-D-glucopyranoside; andoctyl-β-D-thioglucopyranoside. Another preferred wetting agent isp-isononylphenoxypoly(glycidol), also known as Olin-10G or Surfactant10-G (commercially available as 10G from Olin Chemicals). Two or morewetting agents can be used in combination.

(iv) Tonicity or Osmolality Agents

The porous drug matrices may include one or more tonicity agents, suchas salts (e.g., as sodium chloride or potassium chloride) or sugars(such as mannitol, dextrose, sucrose, or trehalose) to adjust ahypotonic solution of a drug to isotonic so that the drug, when insolution, is physiologically compatible with the cells of the bodytissue of the patient. The type and amount of tonicity agent can beselected by one of skill in the art using known techniques.

(v) PEG lated Excipients

In one embodiment, the matrix further includes a pegylated excipient.Such pegylated excipients include, but are not limited to, pegylatedphospholipids, pegylated proteins, pegylated peptides, pegylated sugars,pegylated polysaccharides, pegylated block-co-polymers with one of theblocks being PEG, and pegylated hydrophobic compounds such as pegylatedcholesterol. The pegylated excipient beneficially envelops or shieldsthe drug from macrophage uptake, which prolongs its half-life orenhances bioavailability of the drug.

Representative examples of pegylated phospholipids include1,2-diacylsn-glycero-3-phosphoethanolamine-N-[Poly(ethylene glycol)2000] (“PEG 2000 PE”) and1,2-diacyl-sn-glycero-3-phosphoethanolamine-N-[Poly(ethylene glycol)5000] (“PEG 5000 PE”), where the acyl group is selected, for example,from dimyristoyl, dipalmitoyl, distearoyl, diolcoyl, and1-palmitoyl-2-oleoyl.

Other polyalkyleneoxides can be used in the place of the polyethyleneglycol moiety.

II. Volatile Solvents

The choice of solvent depends on the drug. In a preferred embodiment,the solvent is an organic solvent that is volatile, has a relatively lowboiling point, or can be removed under vacuum, and which is acceptablefor administration to humans in trace amounts. Representative solventsinclude acetic acid, acetaldehyde dimethyl acetal, acetone,acetonitrile, chloroform, chlorofluorocarbons, dichloromethane, dipropylether, diisopropyl ether, N,N-dimethlyformamide (DMF), foramide,demethyl sulfoxide (DMSO), dioxane, ethanol, ethyl acetate, ethylformate, ethyl vinyl ether, methyl ethyl ketone (MEK), glycerol,heptane, hexane, isopropanol, methanol, isopropanol, butanol,triethylamine, nitromethane, octane, pentane, tetrofuran (THF), toluene,1,1,1-trichloroethane, 1,1,2-trichloroethylene, water, xlene, andcombinations thereof. In general, the drug is dissolved in the volatilesolvent to form a drug solution having a concentration of between 0.01and 80% weight to volume (w/v), more preferably between 0.025 and 30%(w/v).

When the drug is a water soluble drug, aqueous solvents or mixtures ofaqueous and organic solvents, such as water-alcohol mixtures, can beused to dissolve the drug.

III. Pore Forming Agents

Pore forming agents are volatile materials that are used during theprocess to create porosity in the resultant matrix. The pore formingagent can be a volatilizable solid or volatilizable liquid.

1. Liquid Pore Forming Agent

The liquid pore forming agent must be immiscible with the drug solventand volatilizable under processing conditions compatible with the drug.To effect pore formation, the pore forming agent first is emulsifiedwith the drug solvent. Then, the emulsion is further processed to removethe drug solvent and the pore forming agent simultaneously orsequentially using evaporation, vacuum drying, spray drying, fluid beddrying, lyophilization, or a combination of these techniques.

The selection of liquid pore forming agents will depend on the drugsolvent. Representative liquid pore forming agents include water;dichloromethane; alcohols such as ethanol, methanol, or isopropanol;acetone; ethyl acetate; ethyl formate; dimethylsulfoxide; acetonitrile;toluene; xylene; dimethylforamide; ethers such as THF, diethyl ether, ordioxane; triethylatnine; foramide; acetic acid; methyl ethyl ketone;pyridine; hexane; pentane; furan; water; and cyclohexane.

The liquid pore forming agent is used in an amount that is between 1 and50% (v/v), preferably between 5 and 25% (v/v), of the drug solventemulsion.

2. Solid Pore Forming Agent

The solid pore forming agent must be volatilizable under processingconditions which do not harm the drug compositions. The solid poreforming agent can be (i) dissolved in the drug solution, (ii) dissolvedin a solvent which is not miscible with the drug solvent to form asolution which is then emulsified with the drug solution, or (iii) addedas solid particulates to the drug solution. The solution, emulsion, orsuspension of the pore forming agent in the drug solution then isfurther processed to remove the drug solvent, the pore forming agent,and, if appropriate, the solvent for the pore forming agentsimultaneously or sequentially using evaporation, spray drying, fluidbed drying, lyophilization, vacuum drying, or a combination of thesetechniques.

In a preferred embodiment, the solid pore forming agent is a volatilesalt, such as salts of volatile bases combined with volatile acids.Volatile salts are materials that can transform from a solid or liquidto a gaseous state using added heat and/or vacuum. Examples of volatilebases include ammonia, methylamine, ethylamine, dimethylamine,diethylamine, methylethylamine, trimethylamine, triethylamine, andpyridine. Examples of volatile acids include carbonic acid, hydrochloricacid, hydrobromic acid, hydroiodic acid, formic acid, acetic acid,propionic acid, butyric acid, and benzoic acid. Preferred volatile saltsinclude ammonium bicarbonate, ammonium acetate, ammonium chloride,ammonium benzoate and mixtures thereof

Other examples of solid pore forming agents include iodine, phenol,benzoic acid (as acid not as salt), and naphthalene.

The solid pore forming agent is used in an amount between 5 and 1000%(w/w), preferably between 10 and 600% (w/w), and more preferably between10 and 100% (w/w), of the drug.

IV. Method of Making the Porous Drug Matrix

The porous drug matrices preferably are made by (i) dissolving a drug,preferably one having low aqueous solubility, in a volatile solvent toform a drug solution, (ii) combining at least one pore forming agentwith the drug solution to form an emulsion, suspension, or secondsolution, and (iii) removing the volatile solvent and pore forming agentfrom the emulsion, suspension, or second solution. In a preferredembodiment, spray drying, optionally followed by lyophilization orvacuum drying, is used to remove the solvents and the pore formingagent. The removal of the pore forming agent can be conductedsimultaneously with or following removal of enough solvent to solidifythe droplets. Production can be carried out using continuous, batch, orsemicontinuous processes.

First, the selected drug is dissolved in an appropriate solvent. Theconcentration of the drug in the resulting drug solution typically isbetween about 0.01 and 80% (w/v), preferably between about 0.025 and 30%(w/v).

Next, the drug solution is combined, typically under mixing conditions,with the pore forming agent or solution thereof. If a liquid poreforming agent is used, it is first emulsified with the drug solution toform droplets of pore forming agent dispersed throughout the drugsolution. If a solid pore forming agent is used, it is dissolved eitherdirectly in the drug solution to form a solution of drug/pore formingagent, or it is first dissolved in a second solvent which is immisciblewith the drug solvent to form a solution which subsequently isemulsified with the drug solution to form droplets of the pore formingagent solution dispersed throughout the drug solution. A solid poreforming agent alternatively can be added directly to the drug solutionas solid particulates, preferably between about 100 nm and 10 μm insize, to form a suspension of pore forming agent in the drug solution.Subsequently, the solid pore forming agent particle size can be reducedby further processing the resulting suspension, for example, usinghomogenization or sonication techniques known in the art.

Then, the solution, emulsion, or suspension is further processed toremove the drug solvent and the pore forming agent simultaneously orsequentially, using evaporation, spray drying, fluid bed drying,lyophilization, vacuum drying, or a combination of these techniques. Ina preferred embodiment, the solution, emulsion, or suspension isspray-dried. As used herein,“spray dry” means to atomize the solution,emulsion, or suspension to form a fine mist of droplets (of drugsolution having solid or liquid pore forming agent dispersedthroughout), which immediately enter a drying chamber (e.g., a vessel,tank, tubing, or coil) where they contact a drying gas. The solvent andpore forming agents evaporate from the droplets into the drying gas tosolidify the droplets, simultaneously forming pores throughout thesolid. The solid (typically in a powder, particulate form) then isseparated from the drying gas and collected.

The temperature of the inlet and outlet ports of the drying chamber, aswell as the flow rates of the feed solution, atomization gas, and dryinggas, can be controlled to produce the desired products. In aparticularly preferred embodiment, the spray drying methods described inU.S. Pat. No. 5,853,698 to Straub et al., which is hereby incorporatedby reference, are adapted to make the drug matrices described herein.

The drug present in the solids or powder produced may be in acrystalline or an amorphous state, or may be mixture of such states. Thestated generally depends on how the droplets are dried and theexcipients present.

Emulsion Stabilization

In embodiments in which at least one pore forming agent is combined withthe drug solution to form an emulsion, a surfactant or emulsifying agentcan be added to enhance the stability of the emulsion. A variety ofsurfactants may be incorporated in this process, preferably to an amountbetween 0.1 and 5% by weight. Exemplary emulsifiers or surfactants whichmay be used include most physiologically acceptable emulsifiers, forinstance egg lecithin or soya bean lecithin, or synthetic lecithins suchas saturated synthetic lecithins, for example, dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidyl choline or distearoyl phosphatidylcholine or unsaturated synthetic lecithins, such as dioleyl phosphatidylcholine or dilinoleyl phosphatidyl choline. Other hydrophobic oramphipathic compounds can be used in place of the phospholipid, forexample, cholesterol. Emulsifiers also include surfactants such as freefatty acids, esters of fatty acids with polyoxyalkylene compounds likepolyoxpropylene glycol and polyoxyethylene glycol; ethers of fattyalcohols with polyoxyalkylene glycols; esters of fatty acids withpolyoxyalkylated sorbitan; soaps; glycerol-polyalkylene stearate;glycerol-polyoxyethylene ricinoleate; homo- and co-polymers ofpolyalkylene glycols; polyethoxylated soya-oil and castor oil as well ashydrogenated derivatives; ethers and esters of sucrose or othercarbohydrates with fatty acids, fatty alcohols, these being optionallypolyoxyalkylated; mono-, di- and tri-glycerides of saturated orunsaturated fatty acids, glycerides of soya-oil and sucrose.

Other emulsifiers include natural and synthetic forms of bile salts orbile acids, both conjugated with amino acids and unconjugated such astaurodeoxycholate and cholic acid.

V. Porous Drug Matrix Applications

The porous drug matrices described herein are useful in formulations foradministration to a patient in need of the drug. As usedherein,“patient” refers to animals, including mammals, preferablyhumans. The formulations deliver a therapeutically or prophylacticallyeffective amount of the drug to the patient.

The porous matrices, or formulations thereof, are suitable foradministration of drug by a variety of routes, for example, parenteral,mucosal, oral, topical/transdermal administration, for local, regional,or systemic effect. Examples of parenteral routes include intraveneous,intraarterial, intracardiac, intrathecal, intraosseous, intraarticular,intrasynovial, intracutaneous, subcutaneous, and intramuscularadministration. Examples of mucosal routes include pulmonary(intrarespiratory), buccal, sublingual, intranasal, rectal, and vaginaladministration. The porous matrices also can be formulated forintraocular, conjunctival, aural, urethral, intracranial, intralesional,and intratumoral administration.

In a preferred embodiment, the drug matrix is in the form of powder,which can be reconstituted with an aqueous medium, such as physiologicalsaline, and administered parenterally, such as intramuscularly,subcutaneously, or intravenously. An advantage of the formulationsdescribed herein is that they can be used to convert drugs which must beinfused (e.g., to avoid precipitation of the drug following bolusinjection) to a bolus formulation, avoiding unacceptable precipitationof drug in vivo or for local delivery.

Alternatively, the matrix can be further processed using standardtechniques into tablets or capsules for oral administration, into rectalsuppositories, into a dry powder inhaler for pulmonary administration,or mixed/processed into a cream or ointment for topical administration.These standard techniques are described, for example, in Ansel, et al.,“Pharmaceutical Dosage Forms and Drug Delivery Systems,” 6th Ed.,(Williams & Wilkins 1995), which is incorporated herein by reference.

The present invention will be further understood with reference to thefollowing non-limiting examples.

Overview

Examples 1-10 demonstrate production of porous drug matrices usingdifferent pore forming agents, different drugs, and different solvents.Examples 1-8 use emulsion formulations to produce the matrices, whereasExamples 9 and 10 use solution formulations to produce the matrices.

Examples 11-13 describe the analyses which were used to characterize theporous drug matrices produced in Examples 1-10. These characteristicsinclude density, drug integrity, and dissolution properties. Example 14describes particle size analysis and surface area analysis of low watersolubility drug particles incorporated into the porous drug matrices.

Examples 15-17 describe experiments demonstrating the increased internalsurface area of porous drug matrices produced with pore forming agents.Examples 18-21 describe experiments demonstrating the advantage or needto include a wetting agent as a component of the porous drug matrices.

Example 22 describes an experiment demonstrating the administration ofporous drug matrices as an intravenous bolus.

Examples 23 and 24 describe the production of porous drug matricesproduced with pore forming agents and pegylated phospholipids.

Materials and Equipment

The following materials and equipment were used in the examples. PEG3350, PEG 8000, polyvinylpyrrolidone K-15, nifedipine, naproxen,prednisone, SPAN™ 40, lecithin, TWEEN™ 80, PLURONIC™ 127, ammoniumchloride, ammonium bicarbonate, and ammonium acetate were obtained fromSpectrum Chemicals (Gardena, Calif.). Griseofalvin was obtained fromAldrich Chemicals (Milwaukee, Wis.). Taxol was obtained from Hauser(Boulder, Colo.).1,2-Dimyristoyl-sn-Glycero-3-Phosphoethanolamine-N-[Poly(ethylenegloycol-5000] (PEG 5000 PE) and1,2-Dimyristoyl-sn-Glycero-3-Phosphoethanolamine-N-[Poly(ethyleneglycol)-2000] (PEG 2000 PE) were obtained from Avanti Polar Lipids Inc.(Alabaster, Ala.). Methylene chloride was obtained from EM Science(Gibbstown, N.J.). All emulsions were produced using a Virtis IQ²homogenizer (Virtis, Gardiner, N.Y.). Formulations were spray dried on abenchtop spray dryer using an air atomizing nozzle.

EXAMPLE 1 Production of a Porous Prednisone Matrix Using AmmoniumBicarbonate as a Pore Forming Agent with SPAN™ 40 and PEG 8000 asWetting Agents

5.46 g of PEG 8000, 0.545 g of prednisone, and 0.055 g of SPAN™ 40 weredissolved in 182 mL of methylene chloride. An aqueous solution wasprepared by dissolving 3.27 g of ammonium bicarbonate in 18.2 mL ofdeionized (DI) water. The aqueous solution was added to the organicsolution (phase ratio 1:10) and homogenized for 5 minutes at 16,000 RPM.The resulting emulsion was spray dried on a benchtop spray dryer usingan air-atomizing nozzle and nitrogen as the drying gas. Spray dryingprocess conditions were 20 ML/min solution flow rate, 60 kg/hr dryinggas rate, and 36° C. outlet temperature.

EXAMPLE 2 Production of a Porous Prednisone Matrix Using AmmoniumBicarbonate as a Pore Forming Agent With PEG 8000, TWEEN™ 80, Lecithinas Wetting Agents

5.46 g of PEG 8000, 0.545 g of prednisone, 0.003 g of TWEEN™ 80, and0.003 g of lecithin were dissolved in 182 mL of methylene chloride. Anaqueous solution was prepared as described in Example 1. The aqueoussolution was added to the organic solution (phase ratio 1:10) andhomogenized for 15 minutes as described in Example 1. The resultingemulsion was spray dried as described in Example 1 using processconditions of 20 mL/min solution flow rate, 60 kg/hr drying gas rate,and 35° C. outlet temperature.

EXAMPLE 3 Production of a Porous Prednisone Matrix Using AmmoniumAcetate as a Pore Forming Agent, and PEG 8000, TWEEN™ 80, and Lecithinas Wetting Agents

A prednisone-loaded organic solution was prepared as described inExample 2. An aqueous solution was prepared by dissolving 3.27 g ofammonium acetate in 18.2 mL of DI water. The aqueous and organicsolutions were homogenized and spray dried as described in Example 2.

EXAMPLE 4 Production of a Porous Prednisone Matrix Using AmmoniumChloride as a Pore Forming Agent, and PEG 8000, TWEEN™ 80, and Lecithinas Wetting Agents

A prednisone-loaded organic solution was prepared as described inExample 2. An aqueous solution was prepared by dissolving 3.27 g ofammonium chloride in 18.2 mL of DI water. The aqueous and organicsolutions were homogenized as described in Example 1. The resultingemulsion was spray dried as described in Example 2.

EXAMPLE 5 Production of a Porous Griseofulvin Matrix Using AmmoniumBicarbonate as a Pore Forming Agent, and PEG 3350, TWEEN™ 80, andLecithin as Wetting Agents

9.09 g of PEG 3350, 4.55 g of griseofulvin, 0.01 g of TWEEN™ 80, and0.01 g of lecithin were dissolved in 182 mL of methylene chloride. Anaqueous solution was prepared by dissolving 3.27 g of ammoniumbicarbonate and 1.09 g of PEG 3350 in 18.2 mL of DI water. The aqueousand organic solutions were homogenized as described in Example 1. Theresulting emulsion was spray dried as described in Example 1 usingprocess conditions of 20 ml/min solution flow rate, 80 kg/hr drying gasrate, and 12° C. outlet temperature.

EXAMPLE 6 Production of a Porous Nifedipine Matrix Using AmmoniumBicarbonate as a Pore Forming Agent, and PEG 3350 and Lecithin asWetting Agents

9.09 g of PEG 3350, 2.27 g of nifedipine, and 0.009 g of lecithin weredissolved in 182 mL of methylene chloride. An aqueous solution wasprepared by dissolving 3.27 g of ammonium bicarbonate in 18.2 mL of DIwater. The aqueous and organic solutions were homogenized in describedin Example 1. The resulting emulsion was spray dried as described inExample 1 using process conditions of 20 ml/min solution flow rate, 60kg/hr drying gas rate, and 20° C. outlet temperature.

EXAMPLE 7 Production of a Porous Naproxen Matrix Using Ammonium Chlorideas a Pore Forming Agent, and PEG 3350 and Lecithin as Wetting Agents

A naproxen-loaded organic solution was prepared by dissolving 10.91 g ofPEG 3350, 2.73 g of naproxen, and 0.109 g of lecithin in 182 mL ofmethylene chloride. An aqueous solution was prepared as described inExample 4. The aqueous and organic solutions were homogenized asdescribed in Example 1, and the resulting emulsion was spray dried usingprocess conditions of 20 m/min solution flow rate, 100 kg/hr drying gasrate, and 20° C. outlet temperature.

EXAMPLE 8 Production of a Porous Paclitaxel Matrix Using AmmoniumBicarbonate as a Pore Forming Agent, and PEG 3350 and Lecithin asWetting Agents

A paclitaxel-loaded organic solution was prepared by dissolving 3.0 g ofpaclitaxel, 15.0 g of PEG 3350, and 15.7 mg of lecithin in 100 mL ofmethylene chloride. An aqueous solution composed of 1.8 g of ammoniumbicarbonate and, 0.6 g of PEG 3350 in 10 mL of DI water was added to theorganic solution (phase ratio 1:10). The mixture was homogenized for 5minutes at 16,000 RPM. The resulting emulsion was spray dried usingprocess conditions of 10 mL/min solution flow rate, 60 kg/hr drying gasrate, and 25° C. outlet temperature.

EXAMPLE 9 Production of a Porous Nifedipine Matrix Using AmmoniumBicarbonate as a Pore Forming Agent, PEG 3350 and TWEEN™ 80 as WettingAgents, Polyvinylpyrrolidone as a Bulking Agent, and Ethanol as aSolvent

A nifedipine-loaded organic solution was prepared by dissolving 0.76 gof nifedipine, 0.28 g of PEG 3350, and 2.72 g of polyvinylpyrrolidoneK-15 in 170 mL of ethanol. An aqueous solution composed of 1.62 g ofammonium bicarbonate and 3 mg of TWEEN™ 80 in 30 mL of DI water wasadded to the ethanol solution and mixed. The resulting solution wasspray dried using process conditions of 20 mL/min solution flow rate,100 kg/hr drying gas rate, and 36° C. outlet temperature.

EXAMPLE 10 Production of a Porous Nifedipine Matrix Using AmmoniumBicarbonate as a Pore Forming Agent, PEG 3350 and PLURONIC™ F127 asWetting Agents, Polyvinylpyrrolidone as a Bulking Agent, and Ethanol asa Solvent

A nifedipine-loaded organic solution was prepared by dissolving 0.76 gof nifedipine, 0.28 g of PEG 3350, and 2.72 g of polyvinylpyrrolidoneK-15 in 170 mL of ethanol. An aqueous solution composed of 1.62 g ofammonium bicarbonate and 3 mg of PLURONIC™ F127 in 30 mL of DI water wasadded to the ethanol solution and mixed. The resulting solution wasspray dried using process conditions of 20 mL/min solution flow rate,100 kg/hr drying gas rate, and 36° C. outlet temperature.

EXAMPLE 11 In Vitro Dissolution of Porous Drug Matrices

The in vitro dissolution rates of the powders produced in Examples 1-10were compared to the dissolution rates of the bulk drug of interest.

Analytical Method

All dissolution studies were conducted in PBS (phosphate bufferedsaline) at room temperature in a glass beaker using overhead mixing. Themixer used was an IKARW16 Basic Mixer with a R1342 impeller shaftrunning at stirring rate 5. Samples were removed via pipet, filteredthrough 0.22 micron CA syringe filter, and then analyzed. UV-visspectroscopy was conducted on an Hewlett Packard Model 8453. Dissolutioncurves are presented as percent of complete dissolution.

For griseofalvin, PBS (600 mL) was added to an appropriate amount ofmaterial being tested to contain 2.4 mg of griseofulvin. UV analysis wasperformed at 291 nm.

For naproxen, PBS (100 mL) was added to an appropriate amount ofmaterial being tested to contain 100 mg of naproxen. All vesselscontaining naproxen as a solid or as a solution were protected fromlight. UV analysis was performed at 332 nm.

For nifedipine, PBS (600 mL) was added to an appropriate amount ofmaterial being tested to contain 2.4 mg of nifedipine. All vesselscontaining nifedipine as a solid or in solution were protected fromlight. UV analysis was performed at 237 nm.

For prednisone, PBS (250 mL) was added to an appropriate amount ofmaterial being tested to contain 5 mg of prednisone. UV analysis wasperformed at 244 nm.

For paclitaxel, studies were conducted in PBS containing 0.08% TWEEN™ 80(T80/PBS). T80/PBS (10 mL) was added to an appropriate amount ofmaterial being tested to contain 5 mg of paclitaxel in a 15 mLpolypropylene conical tube, and the suspension was vortexed for 3-4minutes. The suspension (0.25 mL) was then added to 250 mL of T80/PBS ina 600 mL glass beaker for dissolution analysis. HPLC analysis wasperformed directly on the filtered aqueous solutions using thepaclitaxel HPLC method described in Example 13.

Results

The in vitro dissolution rates of the porous drug matrices produced inexamples 1-10 are provided in FIGS. 1-6. The in vitro dissolution of theporous drug matrices are compared to the bulk drug of interest. In allcases, the time for 80% dissolution of the porous drug matrices is 4-50times shorter than the time for 80% of the bulk drug to dissolve. Therate of dissolution which is approximated as the slope of the curve is10 to 1400 times greater for the porous drug matrices of Examples 1-10as compared to the specific bulk drug of interest.

EXAMPLE 12 Density of Porous Drug Matrices

The densities of the dry powder produced in Examples 1-7 are summarizedin Table 1. Density was measured using Transaxial Pressure (“TAP”) witha Micromeritics GeoPyc 1360 using a consolidation force of 8 Newtons.The matrices are less dense than the starting bulk drug in all cases,indicating that the porous drug matrices are more porous than thecommercially available bulk drug.

TABLE 1 Particle Density Analysis Density Material (g/mL) PrednisoneBulk 0.68 Example 1 0.48 Example 2 0.55 Example 3 0.51 Example 4 0.49Griseofulvin Bulk 0.80 Example 5 0.55 Nifedipine Bulk 1.01 Example 60.56 Naproxen Bulk 0.69 Example 7 0.58

EXAMPLE 13 Integrity of the Drug in Porous Drug Matrices

Analytical Method

Drug integrity post processing was assessed by High Pressure LiquidChromatography (“HPLC”) (Hewlett Packard Series 1100 HPLC). USPchromatography conditions were used for prednisone, naproxen,nifedipine, and griseofulvin. Vessels and vials containing naproxen ornifedipine solutions were protected from light. For paclitaxel, thechromatographic conditions included a Nucleosil column (5:m, C18, 100A,250×4.6 mm), a mobile phase of 2 mM H₃PO₄/Acetonitrile (2:3) at a flowrate of 1.5 mL/min, UV detection at 227 nm, and a run time of 25 min.

Results

The integrities of the drugs following the processing in Examples 1-9are shown in Table 2 as purities. The process of forming the drug intoporous matrices does not appear to alter the purity of the drug.

TABLE 2 Drug Integrity Analysis Purity Material (%) Prednisone Powder100 Example 1 99.8 Example 2 99.8 Example 3 99.8 Example 4 99.8Griseofulvin Bulk 95.7 Example 5 95.7 Nifedipine Bulk 100 Example 6 100Example 9 100 Example 10 100 Naproxen Bulk 100 Example 7 100 PaclitaxelBulk 100 Example 8 100

EXAMPLE 14 Particle Size Analysis and Surface Area Analysis of DrugParticles in Wetted Porous Drug Matrices

Analytical Methods

Particle size analysis was performed using the Coulter Multisizer IIwith a 50 micron aperture using siphon mode. Electrolyte waspre-saturated with the drug of interest, and filtered through a 0.22micron filter prior to addition of lots for analysis to ensure that noportion of the drug within the lot would dissolve during the analysis.

Results

The mean particle size and total surface area of the drug particlesgenerated when the porous drug matrices produced in Examples 1-7 werereconstituted in aqueous media are summarized in Table 3.

TABLE 3 Particle Size and Surface Area Analysis Surface Area Size (m²/mLof Material (microns) microparticles) Prednisone Powder 2.07 1.43Example 1 1.58 1.66 Example 2 1.39 2.53 Example 3 1.39 3.02 Example 41.24 3.36 Griseofulvin Bulk 2.42 0.88 Example 5 2.16 1.28 NifedipineBulk 2.64 0.57 Example 6 1.78 1.98 Naproxen Bulk 2.89 0.66 Example 71.34 2.79

In all cases, the particle size of the drug particles which resultedfrom wetting of the porous drug matrices was reduced relative to thestarting bulk material by 10 to 54%, and the total surface area of theparticles was increased relative to the starting bulk drug byapproximately 16-320%.

EXAMPLE 15 Nifedipine Drug Matrices Containing a Wetting Agent ProducedWith and Without a Pore Forming Agent

A nifedipine/PEG solution was prepared by dissolving 2.0 g ofnifedipine, 8.0 g of PEG 3350, and 8 mg of lecithin in 200 mL ofmethylene chloride (Example 15A). A second identical nifedipine-loadedorganic solution was prepared. An aqueous solution composed of 1.8 g ofammonium bicarbonate in 20 mL of DI water was added to the firstnifedipine organic solution (phase ratio 1:10). The mixture washomogenized for 5 minutes at 16,000 RPM. The nifedipine solution(Example 15A) and the nifedipine emulsion (Example 15B) were separatelyspray dried using process conditions of 20 mL/min solution flow rate, 60kg/hr drying gas rate, and 21° C. outlet temperature.

EXAMPLE 16 Griseofulvin Drug Matrices Containing a Wetting AgentProduced With and Without a Pore Forming Agent

A griseofulvin/PEG solution was prepared by dissolving 5.0 g ofgriseofulvin, 11.2 g of PEG 3350, 11 mg of TWEEN™ 80, and 11 mg oflecithin in 200 mL of methylene chloride (Example 16A). A secondidentical griseofulvin-loaded organic solution was prepared. An aqueoussolution composed of 1.8 g of ammonium bicarbonate in 20 mL of DI waterwas added to the first organic solution (phase ratio 1:10). The mixturewas homogenized for 5 minutes at 16,000 RPM. The griseofulvin solution(Example 16A) and griseofulvin emulsion (Example 16B) were spray driedon a benchtop spray dryer using process conditions of 20 mL/min solutionflow rate, 80 kg/hr drying gas rate, and 13° C. outlet temperature.

EXAMPLE 17 Internal Surface Area of Porous Drug Matrices Containing aWetting Agent and Produced With and Without a Pore Forming Agent

The internal surface areas of the drug matrices produced in Examples 15and 16 were assessed by Krypton BET. BET specific surface area analysiswas performed using multi-point surface area analysis with krypton asthe gas. Samples were outgassed to 20 micron vacuum at 20° C. prior toanalysis.

The results, shown in Table 4, illustrate that the use of the poreforming agent led to an increase of between 2.3 and 3.5 fold in theinternal surface area of the resultant drug matrix.

TABLE 4 Internal Surface Area of Drug Matrices Matrix Surface Area(Example No.) (m²/g matrix) Nifedipine with wetting agent (15A) 0.40Nifedipine with wetting agent and 1.4  Ammonium Bicarbonate (15B)Griseofulvin with wetting agent (16A) 0.41 Griseofulvin with wettingagent and 0.95 Ammonium Bicarbonate (16B)

EXAMPLE 18 Nifedipine Drug Matrix Produced Without a Pore Forming Agentor Wetting Agent

A 5% nifedipine solution was prepared by dissolving 10.0 g of nifedipinein 200 mL of methylene chloride. The solution was spray dried on abenchtop spray dryer using the following conditions: 20 mL/min solutionflow rate, 60 kg/hr drying gas rate, and 22° C. outlet temperature.

EXAMPLE 19 Griseofulvin Drug Matrix Produced Without a Pore FormingAgent or Wetting Agent

An 8.1% griseofulvin solution was prepared by dissolving 16.2 g ofgriseofulvin in 200 mL of methylene chloride. The solution was spraydried on a benchtop spray dryer using process conditions of 20 mL/minsolution flow rate, 80 kg/hr drying gas rate, and 13° C. outlettemperature.

EXAMPLE 20 In Vitro Dissolution of Nifedipine Drug Matrices ProducedWith / Without Pore Forming Agent and Wetting Agent

The in vitro dissolution rates of the nifedipine matrices produced inExamples 15 and 18 are shown in FIG. 6. The in vitro dissolution of thedrug matrices produced with either wetting agent or wetting agent andpore forming agent have increased dissolution rates as compared to thedrug matrix produced with the drug alone. The matrix produced with boththe wetting agent and the pore forming agent has the greatestdissolution rate.

EXAMPLE 21 In Vitro Dissolution of Griseofulvin Drug Matrices ProducedWith/Without Pore Forming Agent and Wetting Agent

The in vitro dissolution rates of the griseofulvin matrices produced inexamples 16 and 19 are provided in FIG. 7. The in vitro dissolution ofthe drug matrices produced with either wetting agent or wetting agentand pore forming agent have increased dissolution rates as compared tothe drug matrix produced with the drug alone. The matrix produced withboth the wetting agent and the pore forming agent has the greatestdissolution rate.

EXAMPLE 22 Administration of Porous Drug Matrices as an IntravenousBolus to Dogs

A nifedipine-loaded organic solution was prepared by dissolving 9.09 gof PEG 3350, 2.27 g of nifedipine, and 0.009 g of lecithin in 182 mL ofmethylene chloride. An aqueous solution was prepared by dissolving 3.27g of ammonium bicarbonate and 0.91 g of PEG 3350 in 18.2 mL of deionizedwater at room temperature. The aqueous and organic solutions werehomogenized as described in Example 1, and the resulting emulsion wasspray dried using process conditions of 20 mL/min solution flow rate, 60kg/hr drying gas rate, and 20° C. outlet temperature.

A suspension of the porous nifedipine drug matrix was prepared in 5%idextrose solution at a concentration of 2.5 mg/mL. The suspension (2mL) was administered as a bolus to four beagle dogs, which weighed 8-10kg. Blood samples were taken at time-points ranging from 1 minute to 24hours. The samples were processed into plasma, were stored frozen, andwere protected from light until analysis via liquid chromatography-massspectrometry.

All animals tolerated the suspension administered as a bolus. Theaverage plasma levels of the intravenously administered suspension isshown in FIG. 8.

EXAMPLE 23 Production of a Porous Nifedipine Matrix Using a PegylatedPhospholipid, 1, 2-Dimyristoyl-sn-Glycero-3Phosphoethanolamine-N-[Poly(ethylene glycol)-5000 ]

A nifedipine-loaded organic solution was prepared by dissolving 2.0 g ofnifedipine, 30.0 g of PEG 3350, 4 mg of lecithin, and 4 mg of 1,2-Dimyristoylsn-Glycero-3-Phosphoethanolamine-N-[Poly(ethleneglycol)-5000] (PEG 5000 PE) in 202 mL of methylene chloride. An aqueoussolution of 1.8 g of ammonium bicarbonate in 20 mL of DI water was addedto the organic solution (phase ratio 1:10). The mixture was homogenizedfor 5 minutes at 16,000 RPM. The resulting emulsion was spray driedusing process conditions of 20 mL/min solution flow rate, 60 kg/hrdrying gas rate, and 21° C. outlet temperature.

EXAMPLE 24 Production of a Porous Nifedipine Matrix Using a PegylatedPhospholipid, 1, 2-Dimyristoyl-sn-Glycero-3Phosphoethanolamine-N-[Poly(ethylene glycol)-2000 ]

A nifedipine-loaded organic solution was prepared by dissolving 2.0 g ofnifedipine, 30.0 g of PEG 3350, 4 mg of lecithin, and 4 mg of 1,2-Dimyristoylsn-Glycero-3-Phosphoethanolamine-N-[Poly(ethleneglycol)-2000] (PEG 2000 PE) in 202 mL of methylene chloride. An aqueoussolution composed of 1.8 g of ammonium bicarbonate in 20 ml of DI waterwas added to the organic solution (phase ratio 1:10). The mixture washomogenized for 5 minutes at 16,000 RPM. The resulting emulsion wasspray dried using process conditions of 20 mL/min solution flow rate, 60kg/hr drying gas rate, and 21° C. outlet temperature.

Modifications and variations of the present invention will be obvious tothose of skill in the art from the foregoing detailed description. Suchmodifications and variations are intended to come within the scope ofthe following claims.

We claim:
 1. A method for making a porous matrix of drug comprising (a)dissolving a drug in a volatile organic solvent to form a drug solution,(b) combining at least one volatile pore forming agent with the volatileorganic drug solution to form an emulsion, suspension, or secondsolution, and (c) removing the volatile organic solvent and volatilepore forming agent from the emulsion, suspension, or second solution toyield the porous matrix comprising drug, wherein the porous matrixcomprising drug has a tap density of less than or equal to 1.0 g/mL or atotal surface area of greater than or equal to 0.2 m²/g.
 2. The methodof claim 1 wherein the drug has low aqueous solubility.
 3. The method ofclaim 1 further comprising incorporating at least one wetting agent intothe emulsion, suspension, or second solution.
 4. The method of claim 1wherein step (c) is conducted using a process selected from spraydrying, evaporation, fluid bed drying, lyophilization, vacuum drying, ora combination thereof.
 5. The method of claim 1 wherein the drugsolution or pore forming agent further comprises excipients selectedfrom the group consisting of hydrophilic excipients, pegylatedexcipients, and tonicity agents.
 6. The method of claim 1 wherein thepore forming agent is a volatile salt.
 7. The method of claim 1 whereinthe volatile salt is selected from the group consisting of ammoniumbicarbonate, ammonium acetate, ammonium chloride, ammonium benzoate, andmixtures thereof.